This invention is concerned with novel 2-[2-pyridinyloxy(thio or amino)methyl]-1H-imidazoles and derivatives or pharmaceutically acceptable salts thereof of structural Formula I ##STR1## which have antidepressant, nasal decongestant and antihypertensive activity. It also relates to a process for preparing the novel compounds, pharmaceutical compositions comprising the novel compounds and to a method of treating depression, and nasal congestion with the novel compounds.
The pyridine group is common among compounds with useful pharmacological properties, such as the 2-piperazinyl-5 (and/or 6)-substituted pyridines of U.S. Pat. No. 4,078,063 which are anorexigenic agents and also said to have antidepressant activity by virtue of their pharmacological influence on serotonin levels.
Now, with the present invention there is provided a group of substituted pyridines of structural Formula I which generally are antidepressants and nasal decongestants by virtue of their ability to selectively antagonize .alpha..sub.2 -adrenergic receptor sites, and to stimulate .alpha..sub.1 -adrenergic receptors.
The concept that the complex clinical state of depression is linked to a functional deficiency of monoamines in the central nervous system is now widely accepted. Numerous biochemical and clinical observations support the proposal that many forms of depressive illness are associated with reductions in adrenergic activity of functionally important sites in the brain. Thus, classical antidepressive drugs, such as amitriptyline and imipramine, are believed to act by blocking the neuronal reuptake of norepinephrine and/or serotonin, thereby enhancing the availability of the monoamines as neuro-transmitters.
Combinations of norepinephorine reuptake blockers or monoamine oxidase inhibitors with selective .alpha..sub.2 -adrenergic receptor antagonists, their effects being at least additive, form another aspect of this invention.
In addition of .alpha..sub.1 -adrenergic receptors which mediate postsynaptic responses to the neurotransmitter norepinephrine, other adrenergic receptors are present at or near sympathetic terminals. These latter receptors, .alpha..sub.2 -adrenergic receptors, form part of a negative feedback system which modulates noradrenergic neurotransmission by controlling the impulse-induced release of norepinephrine from presynaptic terminals. Activation of .alpha..sub.2 -adrenergic receptors results in a decrease in the amount of norepinephrine normally released from the nerve terminals by nerve impulses while antagonism of .alpha..sub.2 -adrenergic receptors increases norepinephrine release. Therefore, molecules that block .alpha..sub.2 -adrenergic receptors afford an alternate approach to enhancement of noradrenergic function and the treatment of depression associated with an absolute or relative deficiency of adrenergic function.
Mianserin, a clinically effective antidepressant which has been reported to have minimal in vivo norepinephrine reuptake inhibiting properties, blocks .alpha..sub.2 -adrenergic receptors. However, mianserin fails to exhibit any important selectivity for .alpha..sub.1 - or .alpha..sub.2 -adrenergic receptors suggesting that mianserin, in vivo, blocks .alpha..sub.1 -receptors at about the same dose required to block .alpha..sub.2 -receptors (Clineschmidt et al., Arch. Int. Pharmacodyn. Ther., 242, 59 (1979)).
The compounds of the present invention having .alpha..sub.2 properties reduce blood pressure by virtue of their ability to stimulate central adrenergic receptorsites.
The compounds of the present invention, being highly selective .alpha..sub.2 -adrenergic receptor antagonists, have definite therapeutic advantages over the more non-selective .alpha..sub.1 -, .alpha..sub.2 -antagonists. Since .alpha..sub.1 -(or post-synaptic) blockade opposes the increase in nor-adrenergic transmission initiated through .alpha..sub.2 -blockade, compounds that selectively antagonize .alpha..sub.2 -adrenergic receptors induce enhanced neurotransmission at noradrenergic synapses. In addition, molecules with reduced .alpha..sub.1 -adrenergic receptor blocking properties, or with .alpha..sub.1 -adrenergic agonist properties such as the compounds of the present invention, produce less orthostatic hypotension, an undesirable side-effect (Synder, Pharmakopsychiat, 13, 62 (1980)).
Compounds with .alpha..sub.1 -adrenergic agonist properties generally cause marked vasoconstriction and blanching when applied to nasal and pharyngeal mucosal surfaces. This ability to shrink the nasal mucosa makes such compounds useful in the treatment of mucosal congestion accompanying hay fever, allergic rhinitis, sinusitus and other congestive respiratory conditions.
The compounds of the present invention in addition to being .alpha..sub.1 -adrenergic agonists are also .alpha..sub.2 -adrenergic antagonists. The ability to block presynaptic .alpha..sub.2 -adrenergic receptors increases norepinephrine release which augments the shrinking of the nasal mucosa caused by the postsynaptic .alpha..sub.1 -adrenergic stimulation.
As stated previously the novel compounds of formula I generally are .alpha..sub.2 -antagonists/.alpha..sub.1 -agonists thereby manifesting antidepressant and nasal decongestant properties.